Despite more effective chemotherapy combined with limb-salvage surgery for the osteosarcoma treatment, survival rates for osteosarcoma patients have stagnated over the past three decades due to the poor prognosis. Osteosarcoma cancer stem cells (OSCs) are responsible for the growth and metastasis of osteosarcoma. The existence of OSCs offers a theoretical explanation for therapeutic failures including tumor recurrence, metastasis, and drug resistance. Understanding the pathways that regulate properties of OSCs may shed light on mechanisms that lead to osteosarcoma and suggest better modes of treatment. In this study, we showed that the expression level of Kruppel-like factor 4 (KLF4) is highly associated with human osteosarcoma cancer stemness. KLF4-overexpressed osteosarcoma cells displayed characteristics of OSCs: increased sphere-forming potential, enhanced levels of stemness-associated genes, great chemoresistance to adriamycin and CDDP, as well as more metastasis potential. Inversely, KLF4 knockdown could reduce colony formation in vitro and inhibit tumorigenesis in vivo, supporting an oncogenic role for KLF4 in osteosarcoma pathogenesis. Furthermore, KLF4 was shown to activate the p38 MAPK signaling pathway to promote cancer stemness. Altogether, our studies uncover an essential role for KLF4 in regulation of OSCs and identify KLF4-p38 MAPK axis as a potential therapeutic target for osteosarcoma treatment.

中文翻译：

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KLF4作为癌基因，可促进骨肉瘤细胞中的癌干细胞样特征。

尽管更有效的化学疗法结合肢体挽救手术治疗骨肉瘤，但由于预后较差，骨肉瘤患者的生存率在过去的三十年中一直停滞不前。骨肉瘤癌干细胞（OSC）负责骨肉瘤的生长和转移。OSC的存在为包括肿瘤复发，转移和耐药在内的治疗失败提供了理论解释。了解调节OSC特性的途径可能会阐明导致骨肉瘤的机制并提出更好的治疗方式。在这项研究中，我们表明Kruppel样因子4（KLF4）的表达水平与人类骨肉瘤癌变干度高度相关。KLF4过表达的骨肉瘤细胞表现出OSC的特征：增加了形成球的潜力，增强了与茎相关的基因的水平，增强了对阿霉素和CDDP的化学耐药性，以及更高的转移潜力。相反，KLF4基因敲低可以减少体外菌落形成并在体内抑制肿瘤发生，支持KLF4在骨肉瘤发病机制中的致癌作用。此外，已显示KLF4激活p38 MAPK信号传导途径以促进癌症干。总而言之，我们的研究揭示了KLF4在OSC调节中的重要作用，并确定KLF4-p38 MAPK轴是骨肉瘤治疗的潜在治疗靶标。支持KLF4在骨肉瘤发病机制中的致癌作用。此外，已显示KLF4激活p38 MAPK信号传导途径以促进癌症干。总而言之，我们的研究揭示了KLF4在OSC调节中的重要作用，并确定KLF4-p38 MAPK轴是骨肉瘤治疗的潜在治疗靶标。支持KLF4在骨肉瘤发病机制中的致癌作用。此外，已显示KLF4激活p38 MAPK信号传导途径以促进癌症干。总而言之，我们的研究揭示了KLF4在OSC调节中的重要作用，并确定KLF4-p38 MAPK轴是骨肉瘤治疗的潜在治疗靶标。